Optimizing the detection of N-nitrosamine mutagenicity in the Ames test.

Accurately determining the mutagenicity of small-molecule N-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of N-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

Purpose: FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times.

Methods: Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem.

Pharmaceutical equivalence by design for generic drugs: modified-release products.

The Office of Generic Drugs has ensured the high quality of generic products based upon two requirements: pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD). This paradigm has been used with success toward ensuring quality generic drug products that provide the same therapeutic benefit as the RLD. Drug products have increased in design complexity; as a result, approaches to ensure therapeutic equivalence must evolve to provide assurance of quality generic drug products.

Scientific considerations for generic synthetic salmon calcitonin nasal spray products.

Under the Abbreviated New Drug Application pathway, a proposed generic salmon calcitonin nasal spray is required to demonstrate pharmaceutical equivalence and bioequivalence to the brand-name counterpart or the reference listed drug. This review discusses two important aspects of pharmaceutical equivalence for this synthetic peptide nasal spray product. The first aspect is drug substance sameness, in which a proposed generic salmon calcitonin product is required to demonstrate that it contains the same active ingredient as that in the brand-name counterpart.

Pharmaceutical impurities: regulatory perspective for Abbreviated New Drug Applications.

Impurities in drug substances and drug products have been important regulatory issues in the Office of Generic Drugs by having significant impact on the approvability of Abbreviated New Drug Application (ANDAs). This review begins with a discussion of ANDAs and its similarity/differences with NDAs, highlighting the importance of control of pharmaceutical impurities in generic drug product development and regulatory assessment. An overview of the FDA draft guidance documents "ANDAs: Impurities in Drug Substances" and "ANDAs: Impurities in Drug Products" are provided.

Improved attractants for Mediterranean fruit fly, Ceratitis capitata (Wiedemann): responses of sterile and wild flies to (-) enantiomer of ceralure B1.

Tests were conducted on wild Mediterranean fruit flies, Ceratitis capiata (Wiedemann), in Hawaii, Italy, and Kenya, and on sterile released flies in Florida and California with a new male attractant, (-)-ceralure B1. Compared on an equal dosage basis, Mediterranean fruit fly males were significantly more attracted to the (-)-ceralure B1 than to trimedlure in each of the sites tested except for California. Compared with the standard commercial 2 g trimedlure plug, 10 mg applied on cotton wicks (Kauai) was as attractive to wild males as trimedlure after the first 2 d of the test but not after 7 d.

Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs).

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent. Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand.

Applications of process analytical technology to crystallization processes.

Crystallizations of pharmaceutical active ingredients, particularly those that posses multiple polymorphic forms, are among the most critical and least understood pharmaceutical manufacturing processes. Many process and product failures can be traced to a poor understanding and control of crystallization processes. The Food and Drug Administration's process analytical technology (PAT) initiative is a collaborative effort with industry to introduce new and efficient manufacturing technologies into the pharmaceutical industry.